Each year, millions of Americans develop painful temporomandibular disorders (TMD), and symptoms become chronic for as many as one third of them. Yet, little is known about the antecedents of chronic TMD; instead, the best predictors of chronic TMD are characteristics of pain assessed when the condition has already developed. We propose to analyze data collected before, during and after onset of TMD to investigate how antecedent risk factors unfold over time to influence risk of chronic TMD. We hypothesize that repeated psychological stress elicits changes in pain regulatory systems, causing transition from acute to chronic pain in genetically-susceptible people. In response to PAR-09-182, we plan to use existing data in three add-on studies of the multi-site OPPERA prospective cohort study (Orofacial Pain, Prospective Evaluation and Risk Assessment; NIH/NIDCR U01-DE017018). OPPERA enrolled, 3,263 people aged 18-44 years who were examined at baseline to confirm absence of TMD. They also completed questionnaires, underwent physiologic testing of pain regulatory systems (i.e. pain sensitivity and autonomic function), and they provided a sample of blood from which DNA was extracted for genotyping. During the average 3-year follow-up period, quarterly health update questionnaires identified people who developed symptoms, and 258 of them were diagnosed with first-onset TMD. This proposal will analyze three add-on data-collections. 1) The Perceived Stress Scale was added to the quarterly health update questionnaire, providing 31,127 repeated measures of psychological stress among the 2,743 people retained in the cohort. 2) Baseline phenotypic measures were repeated when TMD was first diagnosed in the 258 incident cases. Six months later, the same measures again were repeated, and 85 people were diagnosed with chronic TMD (i.e. duration >6 months). 3) For each incident case, a matched control was selected, and equivalent data were collected at the time the matched case was diagnosed, and six months later. Life course epidemiologic methods will be used to analyze how these repeated measures of perceived stress and pain regulation unfold against the backdrop of people's genetic predisposition, focusing on genes encoding enzymes, neurotransmitters and receptors of the adrenergic system that regulate pain perception. Mixed models for repeated measures and latent growth curve methods will evaluate two qualitatively different pathways by which these risk factors might exert combined effects on risk of chronic TMD: a) an independent risk pathway, in which risk factors exert independent, additive effects; b) an accumulation pathway, in which genes give rise to a cluster of factors involving psychological stress, pain sensitivity and altered autonomic function. To guard against type I error, a sequential set of analyses will restrict tests for gene x phenotype interactions. Based on our preliminary analysis, this strategy provides good power to detect main effects of phenotypes (>0.99) to and sufficient power to detect gene x case-status interactions (0.84) and gene x cumulative stress interactions (0.64).